WO1990003374A1 - 1,4-dihydrothionapthoquinone and heterocyclic congeners which inhibit lipoxygenase enzymes - Google Patents
1,4-dihydrothionapthoquinone and heterocyclic congeners which inhibit lipoxygenase enzymes Download PDFInfo
- Publication number
- WO1990003374A1 WO1990003374A1 PCT/US1989/003492 US8903492W WO9003374A1 WO 1990003374 A1 WO1990003374 A1 WO 1990003374A1 US 8903492 W US8903492 W US 8903492W WO 9003374 A1 WO9003374 A1 WO 9003374A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydrogen
- alkyl
- phx
- compound
- phenyl
- Prior art date
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- 108090000128 Lipoxygenases Proteins 0.000 title abstract description 11
- 125000000623 heterocyclic group Chemical group 0.000 title abstract description 3
- 239000000039 congener Substances 0.000 title description 3
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- -1 amino-substituted phenyl group Chemical group 0.000 claims description 25
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- 238000000034 method Methods 0.000 claims description 22
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 21
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- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- UMNKXPULIDJLSU-UHFFFAOYSA-N dichlorofluoromethane Chemical compound FC(Cl)Cl UMNKXPULIDJLSU-UHFFFAOYSA-N 0.000 description 1
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- 239000008187 granular material Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 238000007912 intraperitoneal administration Methods 0.000 description 1
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- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical class CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- 150000002790 naphthalenes Chemical class 0.000 description 1
- 150000002791 naphthoquinones Chemical class 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- UENWRTRMUIOCKN-UHFFFAOYSA-N phenylmethylmercaptan Natural products SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 230000004044 response Effects 0.000 description 1
- 210000001995 reticulocyte Anatomy 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000000580 secretagogue effect Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
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- 210000004878 submucosal gland Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- UPUJGSUSGASQJV-UHFFFAOYSA-J tetrasodium;disulfite Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])=O.[O-]S([O-])=O UPUJGSUSGASQJV-UHFFFAOYSA-J 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- SWGJCIMEBVHMTA-UHFFFAOYSA-K trisodium;6-oxido-4-sulfo-5-[(4-sulfonatonaphthalen-1-yl)diazenyl]naphthalene-2-sulfonate Chemical compound [Na+].[Na+].[Na+].C1=CC=C2C(N=NC3=C4C(=CC(=CC4=CC=C3O)S([O-])(=O)=O)S([O-])(=O)=O)=CC=C(S([O-])(=O)=O)C2=C1 SWGJCIMEBVHMTA-UHFFFAOYSA-K 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/21—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with the sulfur atom of the thio group bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F11/00—Compounds containing elements of Groups 6 or 16 of the Periodic Table
Definitions
- the present invention provides novel 1,4-dihydrothionatpthoquinone and heterocyclic congeners which are useful as inhibitors of the synthesis of leukotrienes and as inhibitors of the action of lipoxygenase in mammalian metabolism.
- the leukotrienes are a class of unsaturated fatty acid compounds which are derived from arachidonic acid by the action of lipoxygenase. See, e.g., Samuelsson, Trends in Pharmacological Sciences, 5:227 (1980); and Samuelsson, et al., Annu. Rev. Biochem. 47:997-1029 (1978). For a discussion of leukotriene nomenclature, see Samuelsson, et al., Prostaglandins, 19:645 (1980).
- the leukotrienes have been discovered as potent constrictors of human bronchi. That is, certain leukotrienes are mediators of the action of slow-reacting substance of anaphylaxis (SRS-A). See, e.g., Dahlen, Nature, 288:484 (1980). These compounds are therefore important mediators of bronchoconstriction in humans.
- SRS-A slow-reacting substance of anaphylaxis
- leukotrienes as agonists in immediate hypersensitivity and other pathological conditions have led to research into inhibitors of leukotriene biosynthesis and leukotriene antagonists. See, e.g., Corey, et al., Tetrahedron Letters 21:4243 (1980).
- Mucus secreted from submucosal glands and surface at the epithelial cells combines with water to form part of the respiratory tract secretions.
- mucous secretions in the respiratory tract is normal being about 50 to 150 ml per day in man.
- the excessive production of mucus is an important feature of many pulmonary diseases.
- chronic bronchitis the flow of mucus increases up to four times.
- the lack of the ability of the patient to deal with this hyper-production leads to paths of physiological conditions of the airways such as chronic bronchitis, asthma, and cystic fibrosis where there is a defect in consistency in clearance of the mucus. Therefore it is medically desirable to regulate the hypersecretion of mucus (J.G.
- Leukotrienes particularly leukotriene C 4 (LTC 4 ) and leukotriene D 4 (LTD 4 ) have been shown to be potent mucous secretagogues. Both LTC 4 and LTD 4 increase the release of mucus from human airways in vitro.
- LTC 4 and LTD 4 increase the release of mucus from human airways in vitro.
- H.G. Johnson, et al.
- LTC 4 was effective in stimulating mucus release in vivo in the cat but not in vitro on cat trachea tissue.
- FPL 55712 an LTC 4 antagonist when given prior to antigen challenge was effective in reversing the tracheal mucus velocity in patients with a history of bronchial asthma but concluded that the clinical significance of FPL 55712 remains to be demonstrated.
- arachidonic acid In mammalian metabolism, arachidonic acid is transformed to 12-L- hydroperoxy-5,8,10,14-eicosatetraenoic acid by the action of 12-lipoxygenase. See, Hamberg, et al., Proceedings of the National Academy of Science, 71:3400-3404 (1974). Similarly, 5-lipoxygenase transforms arachidonic acid into 5-S-hydroperoxy-6,8,11,14-eicosate- traenoic acid. Thus, an agent which inhibits the action of lipoxygenase would be useful in treating or preventing untoward conditions associated with lipoxygenase products.
- the 15-lipoxygenase reaction using for example arachidonic acid as substitute, provides 15- hydroperoxyeicosatetiaenoic acid (15-HPETE) which can be converted to 14.15-LTA 4 as reduced to 15-hydroxyeicosatetraenoic acid, (T. Schewe, S.M. Rapoport, H. Kuhn, Adv. Enzymol. 58, 191 (1986).
- Both the human epithilial cell and trachea produce large amounts of 15-HETE and its metabolites, (D. Henke, M.R. Knowles, R.
- the pathophysiology of administered 15-HETE include profound increases in mucus production and increases in filtration of polymorphonuclear (PMN) leukocyte cell infiltration into lung tissue (H.G. Johnson, M.L. McNee, F.F. Sun, Am. Rev. Resp. Dis., 131, 917 (1985)).
- PMN polymorphonuclear
- Certain napththaquinones are disclosed as intermediates for the preparation of Vitamin K-type derivatives in U.S. patents 4,374,775 and 4,320,065.
- U.S. patents 4,358,461; 4,388,312; and 4,393,075 disclose certain naphthaquinones as SRS-A and lipoxygenase inhibitors. Intermediates for these latter compounds are disclosed in U.S. patent 4,199,531.
- W.D. wulff, et al. have described the use of Fischer carbene complexes in the preparation of certain hydroquinone mono ethers in Abstracts 88 and 89 from the Fall 1983 American Chemical Society Meeting in Washington D.C. (August 18-19, 1983).
- Certain 1-acetoxy-4-methoxy-naphthalenes are also known.
- 4-methoxy-1-na ⁇ hthalenol, acetate is disclosed in German OLS 2802666.
- the corresponding 2,3-dimethyl compound is disclosed in F.M. Dean, et al., J. Chem. Soc, Perkin Trans. 1(20):2289-94 (1977).
- 4-Methoxy-2- phenyl-1-naphthalenol is disclosed in 0. Gonclalves de Lima, et al., Rev. Inst. Antibiot., Univ. Recife 5(1-2):3-9 (1963).
- the present invention particularly provides:
- R 1 and R 2 are the same or different and are
- (PhX) is phenyl substituted by zero to 3 of the following : (a) (C 1 -C 4 )alkyl,
- n 1, 2, 3, or 4;
- n O, 1, 2, 3, 4, or 5;
- -C(O)AA is the acyl portion derived from any naturally occurring alpha-amino acid
- R 14 and R 15 are the same or different and are:
- R 16 is (C 1 -C 4 ) alkyl
- R 17 and R 18 are the same or different and are:
- W is OCH 3 then Z is (C 1 -C 4 )alkyl.
- a method for treating or preventing the hypersecretion of mucus in the respiratory tract of an allergic or asthmatic patient in need thereof which comprises administering a compound of Formula I to a patient in an amount effective to treat or prevent said hypersecretion of mucus.
- R 3 is COCH 3
- Z is hydrogen
- R 1 and R 2 are both ethyl, phenyl or a phenyl and a methyl or an ethyl ester.
- the compounds of the present invention will be named herein using the Chemical Abstracts numbering system (see Naming and Indexing of Chemical Substances for Chemical Abstracts during the Ninth Collective Period (1972-1976), a reprint of section IV from the Volume 76 Index Guide.)
- D is -CH-CH-
- the compounds are named as naphthalenes.
- D is -N(CH 3 )
- the compounds are named as N- methyl indoles
- D is -O- and -S-
- the compounds are named as benzofurans and benzothiophenes , respectively .
- compounds of this invention are useful to inhibit the formation of slow reacting substance of anaphylaxis (SRS-A) and thus its smooth muscle contracting and secretory effects.
- SRS-A slow reacting substance of anaphylaxis
- the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix (C i -C j ) indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
- (C 1 -C 3 )alkyl refers to alkyl of one to 3 carbon atoms, inclusive, or methyl, ethyl, propyl, and isopropyl.
- alkyl of one to 10 carbon atoms, inclusive are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and isomeric forms thereof.
- C 2 -C 10 alkenyl examples are allyl, 1-methylallyl, 2-methyl- allyl (methallyl), 2-butenyl (crotyl), 3-butenyl, 1,2-dimethylallyl, 1,1-dimethylallyl, 2-ethylallyl, 1-methyl-2-butenyl, 2-methyl-2- butenyl, 3-methyl-2-butenyl, 3-pentenyl, 2,3-dimethyl-2-butenyl, 1,1,2-trimethylallyl, 1,3-dimethyl-2-butenyl, 1-ethyl-2-butenyl, 4- methyl-2-pentenyl, 2-ethyl-2-pentenyl, 4,4-dimethyl-2-pentenyl, 2- heptenyl, 2-octenyl, 5-octenyl, 1,4-dimethyl-1-hexenyl, and the like.
- PhX examples include phenyl, p-chlorophenyl, m-bromophenyl, 2,4- difluorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl,- p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2- methylphenyl, 2 ,4-dichloro-3-methylphenyl, p-nitrophenyl, p-methoxy- phenyl, 3-trifluorophenyl, and 4-hydroxyphenyl.
- acids which are commonly used for salt formation, are hydrochloric acid, hydrobromic acid, hydroiodic acid, raethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, phosphoric acid, acetic acid, propionate acid, succinic acid, para-toluenesulfonic acid, maleic acid, tartaric acid, and lactic acid.
- -C(O)-AA is meant the acyl part of an amino acid including the naturally-occurring acids such as: glycine, alanine, valine, leucine, isoleucine, phenylalanine, lysine, proline, tryptophan, methionine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, ornithine, and histidine, and synthetic derivatives thereof.
- these compounds may be in L or D configuration and are well known and readily available to those skilled in the art.
- AA-COOH would represent the amino acids themselves.
- R 3 is definitions (c), (d), or (e)
- the substituent is an amino acid derivative which may be in the "D” and/or "L” configuration
- the prefixes "D” and “L” are a means of indicating the relative configurations of various optically active compounds, especially carbohydrates.
- the compound glyceraldehyde, CH 2 OHCHOHCHO was selected as a standard of reference, because it Is the simplest carbohydrate - an aldotriose - capable of optical isomerism.
- (+)- Glyceraldehyde was arbitrarily assigned a configuration and was designated D-glyceraldehyde, and (-)-glyceraldehyde was assigned a second configuration and was designated L-glyceraldehyde.
- D D-glyceraldehyde
- L L-glyceraldehyde
- amino acyl compounds of this invention when R 3 is -C(O)- (CR 17 R 18 ) m -(CH 2 ) n -NR 14 R 15 , "C(O)-AA or -C(O)-PhX-NH 2 , are also preferred for drug formulation because they are more easily crystallizable (particularly, the salts) and are more water soluble. On the basis of biological activity and ease of formulation, hydrochloride is preferred.
- novel compounds of this invention have been shown to be active as Inhibitors of the production of 5-lipoxygenase derived leukotrienes and some of the compounds of this invention have been shown to be active as inhibitors of the lipoxygenase enzyme system. Some of these compounds are effective in both systems. All of the compounds of this invention are active as inhibitors of at least one of these two systems. Accordingly, these novel compounds are useful for administration to mammals, including humans, whenever it is desirable medically to inhibit either of these systems. Inhibitors of either system are useful in the treatment of asthma.
- all of the compounds of this invention are useful in the treatment of asthma.
- these compounds are useful as bronchodilators or as inhibitors of mediators such as SRS-A which are released from cells activated by an antigen-antibody complex.
- mediators such as SRS-A which are released from cells activated by an antigen-antibody complex.
- these compounds control spasm and facilitate breathing in conditions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema.
- these compounds are administered in a variety of dosage forms, e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories; parenter- ally, subcutaneously, or intramuscularly, with intravenous administration being preferred in emergency situations, by inhalation in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder.
- dosage forms e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories; parenter- ally, subcutaneously, or intramuscularly, with intravenous administration being preferred in emergency situations, by inhalation in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder.
- Doses in the range of about 0.01 to 50 mg per kg of body weight are used 1 to 4 times a day, the exact dose depending on the age, weight, and condition of the patient and on the frequency
- these compounds can be combined advantageously with other anti-asthmatic agents, such as sympathomimetics (isoproterenol, phenylephrine, ephedrine, etc.); xanthine derivatives (theophylline and aminophylline); and corticosteroids (ACTH and prednisolone).
- sympathomimetics isoproterenol, phenylephrine, ephedrine, etc.
- xanthine derivatives theophylline and aminophylline
- corticosteroids ACTH and prednisolone
- the compounds of this invention are particularly useful in treating asthma, but any allergy wherein slow reacting substance of anaphylaxis (SRSA) is thought to be involved as a pharmacological mediator of anaphylaxis can be treated.
- SRSA slow reacting substance of anaphylaxis
- the compounds can be used for treatment of such conditions as allergic rhinitis, food allergy and urticaria as well as asthma.
- the compounds of this invention are effectively administered to human asthma patients by any covenient route such as oral inhalation, aerosol inhalation, parenterally, (orally, intravenously, interperitoneally), transdermally, topically and the like.
- the amino acyl compounds of this invention are preferred for intravenous infusions and the like. Particularly preferred in this regard Is L-Valine, 1-methylthio-3-n-butyl-4-naphalenyl ester, mono- hydrochloride.
- the non-acyl-amino compounds of this invention are preferred for topical administration.
- the composition can comprise the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane) together with a co-solvent, such as ethanol, flavoring materials and stabilizers.
- a co-solvent such as ethanol, flavoring materials and stabilizers.
- a dispensing agent such as oleyl alcohol.
- the lipoxygenase inhibitor compounds of this invention are useful whenever it is desired to inhibit platelet aggregation, reduce the adhesive character of platelets, and remove or prevent the formation of thrombi in mammals, including man, rabbits, dogs, and rats.
- these compounds are useful in the prevention of myocardial infarcts, to prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions.
- these compounds are administered systemically, e.g., intravenously, subcutaneously, Intramuscularly, and in the form of sterile implants for prolonged action.
- the intravenous route of administration is preferred. Doses in the range about 0.005 to about 20 mg per kg of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of adrainis tration .
- lipoxygenase inhibitor compounds are further useful as additives to blood, blood products, blood substitutes, or other fluids which are used in artificial extracorporeal circulation or perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body.
- isolated body portions e.g., limbs and organs
- aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. This blocking is avoided by the presence of these compounds.
- the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of these at a total steady state dose of about 0.001 to 10 mg per liter of circulating fluid. It is especially useful to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.
- 5-lipoxygenase inhibitors prevent the production of slow-reacting substance of anaphylaxis (SRS-A), now known to be a mixture of leukotrienes.
- SRS-A slow-reacting substance of anaphylaxis
- SRS-A mediates the symptoms and pathophysiology of asthma. See Murphy, et al., Proc. Nat. Acad. Sci. USA, 4275-4279 (1979).
- SRS-A slow-reacting substance of anaphylaxis
- 5-Lipoxygenase products have been implicated In essential hypertension (Chand, et al., Microcirculation 1:111-123 (1981), and gout (Rae, et al., Lancet 1122-1124 (Nov. 20, 1982), indicating that the 5-lipoxygenase inhibitors disclosed herein are useful in treating these conditions as well. Further, neutrophil depletion, such as that induced by 5-lipoxygenase inhibitors, has been shown to cause a significant decrease in infarct size following circumflex artery occlusion. See Romson, et al., Circulation 66:85 (1982). Thus, the 5-lipoxygenase inhibitors herein may be useful in the protection of the myocardium following infarct.
- the lipoxygenase inhibitors of the present invention are also useful for the prevention or treatment of deep vein thrombosis (DVT).
- This method comprises the administration of a compound of the Formula I to a mammal susceptible to DVT.
- deep vein thrombosis By “deep vein thrombosis” (DVT) is meant the thrombosis (clot formation) of the lower limb deep veins (deeply situated veins). Such thrombosis is frequently a result of major surgery, massive trauma, myocardial infarction, neoplasia, and pregnancy.
- the term “deep vein thrombosis” or “DVT” Is meant to encompass the thrombosis resulting from these or any other causes.
- prevention in this context Is meant the total or partial avoidance of clot formation in the deep veins of a mammal.
- the present invention includes the treatment of each of various mammalian species, including humans.
- the present invention is particularly and especially concerned with treating domesticated animals, for example, cattle, dogs, cats and swine.
- domesticated animals for example, cattle, dogs, cats and swine.
- Humans are the most preferred mammals to be treated by the methods of this invention.
- oral formulation and oral administration is, for example, the preferred route for use in humans although parenteral (e.g., intravenous, intraperitoneal, and intramuscular) administration is also employed.
- the dosage regimen for the lipoxygenase inhibitor compounds used to treat deep vein thrombosis will depend on a variety of factors, including the type, age, weight, sex, and medical condition of the mammal, and most Importantly on the risks and probable consequences of deep vein thrombosis. It is within the skill of the attending physician or veterinarian to determine the risks of deep vein thrombosis, and to prescribe an effective amount of the lipoxygenase inhibitors claimed herein.
- the dosage is in the range of about 0.01 to about 1 mg/kg/minute by intravenous infusion, or about 0.1 to about 50 mg/kg/day by oral administration. Equivalent dosages for other routes of administra tion are also employed. Similarly, when other lipoxygenase inhibitors are employed, equipotent doses can be administered based on the compound's comparative potency as demonstrated in the standard laboratory test.
- SRS-A inhibitors e.g., in the treatment of asthma.
- the present invention further provides a method of treating or preventing the hypersecretion of mucus in the airways or the respiratory tract of a patient in need thereof. More particularly, the present invention provides a method for treating or preventing the hypersecretion of mucus in the respiratory tract of patients with bronchial asthma, chronic bronchitis, cystic fibrosis, bronchorrhea, obstructive bronchitis and other disease conditions associated with hyperplasia of mucus secreting cells and increased mucus secretion.
- the method of the present invention finds particular use in warm blooded animals including mammals, such as cattle, horses, rodents, dogs, sheep, pigs, monkeys, cats, humans, and birds.
- the present invention provides a prophylactic as well as therapeutic method of treating hypersecretion of mucus in the airways of a warm blooded animal.
- the quantity of compound of Formula I to be administered is any amount effective in treating or preventing hypersecretion of mucus in the airways of the patient being treated.
- the compounds of Formula I are administered, e.g., intravenously, intramuscularly, topically, by aerosol inhalation, bucally or orally.
- the quantity of compound of Formula I effective in achieving the method here claimed is determined by the particular mode of administration and frequency of administration as well as the age and condition of the patient. Generally the amount of compound administered will range from about 0.001 mg to 10 mg per dose given up to three times per day by aerosol inhalation, with a range from about 0.01 mg to 10 mg per dose being preferred.
- a dose of about 0.01 to 10 ⁇ g/kg/min is administered with intramuscular injection ranging from 0.5 to 15 mg per dose.
- intramuscular injection ranging from 0.5 to 15 mg per dose.
- unit doses of from 1 mg to 100 mg given up to three times per day of compounds of Formula I are effective in practicing the method of the present invention.
- the quantity of compound applied topically is that which will give comparable blood levels of active ingredient when said substance is administered by any of the other various routes of administration.
- the compounds of Formula I are formulated into compositions for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, eye drops, oral solutions or suspensions, and oil in water and water in oil emulsions containing suitable quantities of the compound.
- either solid or fluid unit dosage forms can be prepared.
- the compound of Formula I is mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers.
- Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size.
- Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an acceptable vegetable oil, light liquid petrolatum or other inert oil.
- Fluid unit dosage forms for oral administration such as syrups, elixirs, and suspensions can be prepared.
- the forms can be dissolved In an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form a syrup.
- An elixir is prepared by using a hydroalcoholic (ethanol) vehicle with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent.
- Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.
- a suspending agent such as acacia, tragacanth, methylcellulose and the like.
- fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
- the pharmaceutically useful compound described herein, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
- the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
- adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle.
- the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use.
- Parenteral suspensions can be prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. These compounds can be sterilized by exposure to ethylene oxide or an equivalent gas before suspending in the sterile vehicle.
- a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
- compositions for inhalation useful in practicing the method of present invention are of three basic types: (1) a powder mixture preferably micropulverized with particle size, preferably from about 2 to 5. microns; (2) an aqueous solution to be sprayed with a nebulizer; (3) an aerosol with volatile propellant in a pressurized container.
- the powders are quite simply prepared by mixing a suitable pharmaceutically useful compound of Formula I with a solid base which is compatible with lung tissue, preferably lactose.
- the powders are packaged in a device adapted to emit a measured amount of powder when inhaled through the mouth.
- Aqueous solutions are prepared by dissolving the appropriate compound of the Formula I in water and adding salt to provide an isotonic solution and buffering to a pH compatible with inhalation.
- the solutions are dispersed in a spray device or nebulizer and sprayed into the mouth while inhaling.
- Aerosols are prepared by dissolving an appropriate pharmaceut- ically useful compound of Formula I in water or ethanol and mixing with a volatile propellant and placing in a pressurized container having a metering valve to release a predetermined amount of material.
- the liquefied propellant employed is one which has a boiling point below 65oF at atmospheric pressure.
- the liquefied propellant should be non-toxic.
- suitable liquefied propellants which may be employed are the lower alkanes containing up to 5 carbon atoms, such as butane and pentane, or a lower alkyl chloride, such as methyl, ethyl or propyl chlorides.
- fluorinated and fluorochlorlnated lower alkanes or mixtures thereof such as, dichlorodifluoromethane, dichlorotetrafluoroethane, trichloromonofluoromethane, dichloromono- fluoromethane, monochlorodifluoromethane, trichlorotrifluoroethane, difluoroethane and monochlorotrifluoromethane.
- the compounds can be prepared by reaction of the appropriate chromium carbene complex with an alkyne.
- reaction conditions vary when W is OCH 3 or S(O) q Y.
- a second oxidation step is required to obtain the S(O) q Y group where q is greater than zero.
- Methods for conducting the oxidation of a SY group are well known such as N.J. Leonard, C.R. Johnson, J. Org. Chem., 27, 282 (1962).
- One method can comprise treatment with potassium peroxymonosulfate to prepare the SO 2 Y group.
- a carbene complex of the Formula A-1 is reacted with an acetylene of the Formula A-2 (preferably 1.5 equivalents).
- the cycloaddition of the carbene complex A-1 having the -S(O) q Y group forms the subject product only when BF 3 ⁇ Et 2 O (5 mol eq), Ac 2 O (5 mol eq) and NEt 3 (5 mol eq) are present.
- Conversion of the Ac group to the OH then introduction of the OR 3 group can be done by any conventional means.
- Both Scheme A and B reactions are preferably undertaken in a solvent such as tetrahydrofuran (THF) in an inert atmosphere (e.g., argon).
- a solvent such as tetrahydrofuran (THF) in an inert atmosphere (e.g., argon).
- the reaction temperature is at about 65o C.
- alkynes are well known, readily available compounds or may be prepared by known means. Formation of the acetylated product A-2 where W is OCH 3 is known, for example, see U.S. Patent 4,737,519, Col. 13 through Col 14, herein incorporated by reference.
- an addition funnel with a three-way argon-vacuum inlet was placed 0.5 grams of the tetra-n-butylalkoxide carbene.
- the flask was evacuated and filled with argon three times prior to CH 2 CI 2 addition (38 ml).
- To an addition funnel was introduced a solution of 0.07 ml of acetyl chloride in 8 ml of CH 2 CI 2 .
- the carbene solution was cooled to -40o C and the acetyl chloride solution was added dropwise with vigorous stirring (the funnel was rinsed with CH 2 CI 2 upon complete addition).
- the solution was stirred at -40o C for one hour, then cooled to -78o
- an addition funnel with a three-way argon-vacuum inlet was placed 0.8 grams of the tetra ethylalkoxide carbene and the flask was evacuated and filled with argon three times prior to CH 2 CI 2 addition (35 ml).
- To an addition funnel was introduced a solution of 0.09 ml of acetyl chloride in 8 ml of CH 2 CI 2 , then the carbene solution was cooled to- 40o C before the acetyl chloride solution was added dropwise with vigorous stirring (the funnel was rinsed with CH 2 Cl 2 upon complete addition).
- an addition funnel with a three-way argon-vacuum inlet was placed 0.8 grams of the tetra-n-propylalkoxide carbene and the flask was evacuated and filled with argon three times prior to CH 2 CI 2 addition (35 ml).
- To an addition funnel was introduced a solution of 0.08 ml of acetyl chloride in 8 ml of CH 2 CI 2 .
- the carbene solution was cooled to -40o C before the acetyl chloride solution was added dropwise with vigorous stirring (the funnel was rinsed with CH 2 CI 2 upon complete addition).
- an addition funnel with a three-way argon-vacuum inlet was placed 0.8 grams of the tetra-methylalkoxide carbene and the flask was evacuated and filled with argon three times prior to CH 2 CI 2 addition (35 ml).
- To an addition funnel was introduced a solution of 0.11 ml of acetyl chloride in 8 ml of CH 2 CI 2 .
- the carbene solution was cooled to -40o C before the acetyl chloride solution was added dropwise with vigorous stirring (the funnel was rinsed with CH 2 Cl 2 upon complete addition).
- an addition funnel with a three-way argon-vacuum inlet was placed 27 grams of the tetra-n-butylalkoxide carbene and the flask was evacuated and filled with argon three times prior to CH 2 CI 2 addition (400 ml).
- To an addition funnel was introduced a solution of 3.9 ml of acetyl chloride in 80 ml of CH 2 CI 2 .
- the carbene solution was cooled to -40o C before the acetyl chloride solution was added dropwise with vigorous stirring (the funnel was rinsed with CH 2 CI 2 upon complete addition).
- the carbene complex as prepared in the first step of Example 10 was mixed with 1-hexyne in DMF under argon at 25o C and was heated at 125-130o C (bath temperature) for 6 hrs, then 100o C (bath temperature) for 15 hrs under argon.
- the reaction mixture was cooled and diluted with 800 ml of ether.
- the ether layer was washed with sat. NaCl aq sol. (3 x 300 ml).
- the solvent was removed by rotary evaporation, and the residue was treated with IN HCl aq sol. (25 ml), CH 2 Cl 2 (400 ml), and MeOH (350 ml) at 25o C for 5 hrs.
- Table 2 shows 15-lipoxygenas (15-Lo) inhibition data for various compounds at a 20 ⁇ g/ml unit dose.
- the negative values indicate a percentage increase in 15-Lo products. This result is indicative of an increased production of materials which cross react with the 15- HETE antibodies.
- Table 3 shows 15-lipoxygenase inhibition data (15-Lo) for a set of compounds at various unit doses in ⁇ g/ml
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KR1019900701139A KR900701771A (ko) | 1988-09-28 | 1989-08-18 | 리폭시게나아제 효소를 억제하는 1, 4-디히드로티오나프토퀴논 및 헤테로시클릭 협동 작용물 |
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Cited By (3)
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WO2000010588A2 (en) * | 1998-08-18 | 2000-03-02 | The Regents Of The University Of California | Epidermal growth factor receptor antagonists for treating hypersecretion of mucus in the lungs |
US7226661B2 (en) | 2003-02-03 | 2007-06-05 | Board Of Regents, The University Of Texas System | Synthesis of quinones and phenols on solid support |
US7354894B2 (en) | 1998-08-18 | 2008-04-08 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
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- 1989-08-18 WO PCT/US1989/003492 patent/WO1990003374A1/en not_active Application Discontinuation
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EP0146348A2 (en) * | 1983-12-14 | 1985-06-26 | The Upjohn Company | Substituted naphthalenes, indoles, benzofurans and benzothiophenes as lipoxygenase inhibitors |
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WO2000010588A2 (en) * | 1998-08-18 | 2000-03-02 | The Regents Of The University Of California | Epidermal growth factor receptor antagonists for treating hypersecretion of mucus in the lungs |
WO2000010588A3 (en) * | 1998-08-18 | 2001-05-25 | Univ California | Epidermal growth factor receptor antagonists for treating hypersecretion of mucus in the lungs |
US7354894B2 (en) | 1998-08-18 | 2008-04-08 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
US7358222B2 (en) | 1998-08-18 | 2008-04-15 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
US7531500B2 (en) | 1998-08-18 | 2009-05-12 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
US7700547B2 (en) | 1998-08-18 | 2010-04-20 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
US8048844B1 (en) | 1998-08-18 | 2011-11-01 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
US8071074B2 (en) | 1998-08-18 | 2011-12-06 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
US7226661B2 (en) | 2003-02-03 | 2007-06-05 | Board Of Regents, The University Of Texas System | Synthesis of quinones and phenols on solid support |
Also Published As
Publication number | Publication date |
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KR900701771A (ko) | 1990-12-04 |
AU4203789A (en) | 1990-04-18 |
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